In diseases resulting from accumulation of disease-related factors in blood, particularly in cases where the administration of drugs, for instance, is not sufficiently successful, blood purification by extracorporeal circulation (extracorporeal circulation treatment) is used as an effective therapeutic approach. Extracorporeal circulation treatment is a method of treatment which comprises taking out blood from the body, modifying it in some way or other to remove or ameliorate the disease-related factors such as the causative substances accumulated in the blood, abnormal cells, etc., and returning the blood so modified to the patient.
In the conventional extracorporeal circulation treatment where targets of removal are substances of low molecular weight, the removal by hemodialysis, hemofiltration or hemodialysis-filtration is efficient and has been exploited successfully for removal of the waste substances accumulated in the blood of a patient with a disease of the kidney (renal failure), for instance. For those cases in which the targets of removal are substances having high molecular weights which cannot be removed by hemodialysis or the like, many protocols have been developed and are in routine use for the blood purification by hemoperfusion which comprises separating plasma from blood with a plasma separating membrane or the like in advance and processing the plasma with a body fluid processor. For reducing the concentration of the causative substance present in plasma, several methods inclusive of adsorption, separation with a membrane, and separation by precipitation are known.
As a specific system for extracoporeal circulation treatment in which an adsorbent is used to remove causative substances from plasma, there is a system wherein the adsorbent is packed in a vessel equipped with an inlet and an outlet, the plasma is caused to flow directly into the vessel, and the plasma flowing out is returned to the patient (on-line system) or a system wherein the plasma is transferred to a blood bag or the like filled with the adsorbent in advance and, after mixing, the plasma, recovered by filtering off the adsorbent, is returned to the patient (batch system). From the standpoint of easy handling, the on-line system is used with preference.
Meanwhile, as an extracorporeal circulation treatment utilizing the particles for processing body fluid, a system in which the plasma is not separated from the blood but the blood is directly exposed to the particles for processing body fluid is attracting attention of late for its easy handling. The on-line system in which the blood is directly processed is called the direct hemoperfusion system. In this direct hemoperfusion system, it is necessary that the blood cells may pass through clearances between the particles for processing body fluid in a stable manner and there should be substantially no leakage of foreign matter, such as microparticles, from the body fluid processor. In addition, it must be insured that the blood can be efficiently processed to complete the treatment in a short time not imposing appreciable burdens on the patient and medical staff. However, this is technically not easily feasible.
One of the important factors enabling a stable direct hemoperfusion is the diameter of the particles for processing body fluid. Generally the efficiency of body fluid processing can be improved by reducing the mean particle diameter and increasing the effective surface area of the particles for processing body fluid to be used but if the particle diameter is excessively decreased, the clearance between particles is diminished to interfere with passage of the blood cells so that a stable direct hemoperfurion becomes difficult.
Researches have heretofore been undertaken on the particles for processing body fluid suitable for direct hemoperfusion systems in the aspect of physical and chemical characteristics of the particles for processing body fluid. Japanese Kokai Publication Sho-63-115572, with attention directed to the mean particle diameter and particle size distribution, discloses that the particles so engineered that “the volume mean particle diameter is 80 to 400 μm, that particles accounting for not less than 80 volume % are distributed within ±20% of the volume mean particle diameter, and that the percentage of particles smaller than 74 μm in diameter is not less than 5 volume % while that of particles smaller than 25 μm in diameter is not more than 0.1 volume %”, can be utilized as beads enabling direct hemoperfusion. Japanese Kokai Publication Hei-10-005329 describes that “when a sulfated polysaccharide and/or a salt thereof is coupled to a water-insoluble carrier”, the blood perfusion is improved and the mean particle diameter can be reduced as compared with the intact water-insoluble carrier.
For both of the above artifacts, their utility as the particles for processing body fluid has been studied but in order that these artifacts may be practically useful, it is not only essential that the artifacts as such be satisfactory enough as the particles for processing body fluid but also necessary that body fluid processors prepared by packing these artifacts display satisfactory characteristics.
The important point of any body fluid processor of the direct hemoperfusion type from the standpoint of practical utility is that it shows a favorable passage of the blood cells and the blood can be allowed to flow through it at as high a speed as possible in a stable manner. When these requirements are satisfied, an efficient therapy can be administered in a short session time not imposing any appreciable burden on the patient and medical staff.
The important point of a body fluid processor of the direct hemoperfusion type from safety viewpoints is a low risk of leakage of microparticles from the body fluid processor. When a large amount of microparticles exists in the body fluid processor, the microparticles tend to be carried away by blood from the body fluid processor and find their way into the patient's vascular system to clog the capillary blood vessels. Therefore, if only for the purpose of minimizing the risk of leakage of microparticles, it is ideal to provide a body fluid processor packed with the particles for processing body fluid having no potential of generation of microparticles in a microparticles-free condition. However, since porous particles are often used as the particles for processing body fluid in order that the body fluid processing may be accomplished with efficiency, it is technically difficult to provide the particles for processing body fluid which do not generate microparticles and hence it is virtually impossible to implement such an ideal body fluid processor. Therefore, it is of great importance to pack the particles for processing body fluid with the lowest possible potential of generation of microparticles in as microparticles-free condition as possible and in a manner protected against the generation of microparticles within the body fluid processor even when the processor is subjected to vibrations.
As a means for solving above problems, a method of controlling generation of microparticles is known as disclosed in Japanese Kokoku Publication Sho-61-11620 wherein the “adsorbent is pressed to securely fix it in a column” so that the particles for processing body fluid may not readily move within the body fluid processor. However, in the art described in this patent literature, it is not discussed or explored whether the device is useful as a body fluid processor enabling direct hemoperfusion, that is to say whether the blood can be directly passed through the device in a stable manner. In a body fluid processor of the direct hemoperfusion type, if the particles for processing body fluid are immobilized by pressing, it is likely that the clearance between particles is narrowed to interfere with the free flow of blood or the particles are destroyed by compressive forces to generate microparticles.
Conversely when the particles for processing body fluid are not held stationary but are free to move within the body fluid processor, it may happen that vibrations, for instance, cause collision of the particles for processing body fluid to generate microparticles.
Thus, no sufficient studies have heretofore been undertaken on the body fluid processor enabling direct hemoperfusion from safety and practical utility points of view.